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Fusion Oncoproteins in Childhood Cancers
(FusOnC2) Consortium (U54)
Pre-Application Webinar
RFA-CA-17-049
September 11, 2017
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▪ Accelerate progress in cancer, including prevention & screening
▪ From cutting-edge basic research to wider uptake of standard care
▪ Encourage greater cooperation and collaboration
▪ Break down silos within and between academia, government, and
private sector
▪ Enhance data sharing
▪ Genomic Data Commons
▪ Annotated patient-level clinical data and -omics
Goals: 2016 State of the Union Address
The Cancer Moonshot Initiative
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The Process
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Blue Ribbon Panel Recommendations
A. Establish a network for direct patient involvement
B. Create a translational science network devoted to immunotherapy
C. Develop ways to overcome resistance to therapy
D. Build a national cancer data ecosystem
E. Intensify research on the major drivers of childhood cancer
F. Minimize cancer treatment’s debilitating side effects
G. Expand use of proven prevention and early detection strategies
H. Mine past patient data to predict future patient outcomes
I. Develop a 3D cancer atlas
J. Develop new cancer technologies
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Cancer Funding in 21st Century Cures Act
▪ The cancer research portion is named the Beau Biden Cancer
Moonshot Initiative
▪ Allows implementation of the BRP recommendations
▪ Specifies requirements
▪ Data sharing
▪ Health disparities
“To support cancer research, such as the development of cancer vaccines, the development of more sensitive diagnostic tests for cancer, immunotherapy and the development of combination therapies, research that has the potential to transform the scientific field that has inherently higher risk, and that seeks to address major challenges associated with cancer.”
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Blue Ribbon Panel Pediatric Cancer Working Group Recommendations:
• Enhance our understanding of the molecular and biochemical mechanisms of
transformation driven by fusion oncoproteins, to develop faithful models of these
pediatric cancers, to identify their key dependencies, and to use this information
to develop novel therapeutic approaches that target these mechanisms.
• Use a multi-disciplinary, collaborative approach.
• Focus on fusion oncoproteins found in tumors that have high risk of treatment
failure and for which there has been little progress in identifying targeted agents.
• Fusion oncoproteins that control gene expression or chromatin state are of
particular interest.BRP Peadiatric Cancer Working Group Report (pdf)2016 Blue Ribbon Panel Report (pdf)
Recommendation E:
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Recommendation E: The Big Picture
Bring together these communities (and others)
• proteomics
• structural biology
• genomics/epigenomics
• medicinal chemistry
• experimental therapeutics
• cancer biology
To learn more about the molecular mechanisms of transformation driven by
fusion oncoproteins and apply this knowledge to target identification, small
molecule inhibition, and pre-clinical testing.
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▪ Development of model systems to interrogate the role of fusion oncoproteins
in specific childhood cancers and facilitate the preclinical assessment of
potential therapeutics.
▪ Defining the critical dependencies created by specific fusion oncoproteins
through functional genomic screening.
▪ Defining how fusion oncoproteins influence gene expression to perturb normal
cellular programs and block lineage differentiation and development.
▪ Identifying protein complexes bound to fusion oncoproteins and defining the
three-dimensional structure of the domains within the fusion oncoproteins and
the associated protein complex members.
▪ Identifying small molecules that are able to effectively inhibit activities of
individual fusion oncoproteins, block critical interactions, or selectively lead to
their degradation.
BRP Pediatric Cancer Working Group: Recommended Focus
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Goal of the RFA
• The overall goal is to establish a consortium of collaborating research
teams to advance our understanding of the biology and mechanisms
of action of fusion oncoproteins in pediatric cancers, and to apply this
knowledge towards developing targeted therapeutic approaches.
• The research teams comprising the Fusion Oncoproteins in
Childhood Cancers (FusOnC2) Consortium will take a
comprehensive approach to understanding the biology of fusion
oncoproteins in childhood cancers and will use this information to
inform strategies for therapeutic targeting.
• This FOA focuses on fusion oncoproteins found in tumors that
have high risk of treatment failure and for which there has been
little progress in identifying targeted agents.
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Specific Requirements
▪ Responsive applications must focus on one of the following fusion
oncoproteins:
▪ EWSR1-FLI1 or related EWSR1 fusion oncoproteins (Ewing sarcoma)
▪ PAX-FOXO (alveolar rhabdomyosarcoma)
▪ SYT-SSX (synovial sarcoma)
▪ C11orf95–RELA (ependymoma)
▪ NUP98 fusion proteins that occur in young children with AML.
▪ Teams should select either a single fusion oncoprotein or a small family of
related fusion oncoproteins for comprehensive study that includes both
investigation into biological mechanisms and development of targeted
therapeutics.
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Relevant Areas of Expertise (among others)
▪ proteomics
▪ structural biology
▪ genomics/epigenomics
▪ medicinal chemistry
▪ experimental therapeutics
▪ cancer biology
Multi-institutional collaborations are strongly encouraged to achieve the
breadth of expertise required for a comprehensive approach to
understanding fusion protein mechanisms and therapeutic targeting.
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Examples of potential areas of investigation for the Research Projects
▪ Development of model systems and approaches to interrogate the function of
fusion oncoproteins in specific childhood cancers, including those from
racial/ethnic minority and underserved groups, and to provide preclinical
assessment of potential therapeutics. Genetic models are of particular
interest.
▪ Defining the critical dependencies created by specific fusion oncoproteins
through functional genomic screening (e.g., CRISPR and shRNA) of cell lines
derived from these cancers.
▪ Development of functional assays to measure direct effects of fusion
oncoproteins and potentially yield new opportunities for small molecule
development.
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Examples of potential areas of investigation for the Research Projects (Continued)
▪ Defining how fusion oncoproteins influence gene expression to perturb normal
cellular programs to block lineage differentiation and development.
▪ Identifying protein complexes (and/or post-translational modifications)
associated with fusion oncoproteins and additionally defining the three-
dimensional structure of the domains within the fusion oncoproteins and the
associated interacting protein complex members.
▪ Identifying and developing small molecules able to effectively inhibit activities
of individual fusion oncoproteins, block critical interactions, or selectively lead
to their degradation.
▪ Computer-aided drug discovery to allow structure-based drug design.
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Key Dates
▪ Open Date (Earliest Submission Date): October 15, 2017
▪ Letter of Intent Due Date: October 16, 2017
▪ Application Due Date November 15, 2017
(by 5:00 PM local time of applicant organization)
We strongly suggest that applications be submitted a week in advance!
▪ Scientific Merit Review March 2018
▪ Advisory Council Review May 2018
▪ Earliest Start Date July 2018
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Letter of Intent (LOI)
Due October 16, 2017
Highly encouraged, but not required. Not binding and does not enter into the review.
Standard elements:
• Descriptive title of the project
• Name(s), address(es), telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating Institution(s)
• Number and title of this funding opportunity (RFA-CA-17-049)
Additional recommended information:
• Provide a brief (3-5 sentence) description of the project
• Include relevant expertise and Keywords
Email LOI to [email protected]
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Budget
Application budgets are limited to $2.5 million total costs per year, and need to reflect
the actual needs of the proposed project.
Funds Available and Anticipated # of Awards: The NCI intends to commit
approximately $7 million dollars total cost in FY 2018, contingent upon receiving
scientifically meritorious applications. Up to 3 awards are anticipated from this
solicitation.
Project Period: Not to exceed 5 years.
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Mechanism of Support
U54, Specialized Center--Cooperative Agreement
The spectrum of activities comprises a multidisciplinary attack on a specific
disease entity or biomedical problem area. These differ from program project in
that they are usually developed in response to an announcement of the
programmatic needs of an Institute or Division and subsequently receive
continuous attention from its staff. Centers may also serve as regional or
national resources for special research purposes, with funding component
staff helping to identify appropriate priority needs.
Read Cooperative Agreement Terms
• Oversight by NCI staff
• Participation in FusOnC2 Consortium
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Structure of FusOnC2 Centers:
▪ 3-4 Research Projects that address the mechanisms by which fusion
oncoproteins drive pediatric cancers and/or apply this knowledge to the
development of novel strategies for their therapeutic targeting. They should
closely integrate into the organizing framework and together constitute
a comprehensive approach.
▪ Administrative Core to manage and coordinate all Center research and
activities and serve as the liaisons between the Center and the FusOnC2
Consortium.
▪ Shared Resource Cores (optional) may be established to provide expertise
and resources that support and integrate multiple Research Projects. Each
proposed Core must serve 2 or more Research Projects.
Participation in FusOnC2 Consortium
▪ U54 is a cooperative agreement mechanism.
▪ Grantees are expected to actively participate in a FusOnC2 Consortium
▪ PDs/PIs will serve on the Consortium Steering Committee (SC), the primary governing body of the Consortium, to discuss community issues, set policies, and plan and evaluate activities to meet Program goals.
▪ SC will meet regularly by teleconference, and Consortium members will meet in person at an Annual Program Meeting.
▪ Read cooperative agreement terms carefully.
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Administrative Details
▪ Note on Eligible Applicants: Foreign (non-U.S.) institutions are not
eligible to apply as PD/PI, but foreign components are allowed.
▪ No late applications will be accepted.
▪ U54 is a multicomponent mechanism.
▪ 12 pages for Overall component.
▪ 12 pages for Research Projects
▪ 6 pages for Admin Core and any optional Cores
▪ Do not use appendix to circumvent page limits.
▪ Read all directions carefully!
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Overall Component
▪ Instead of standard sections (significance, innovation, approach), focus
on overall vision and plan for the proposed FusOnC2 Center, including:
▪ Center Organization.
▪ Center Integration.
▪ Center Expertise.
▪ Research Projects.
▪ Shared Resource Cores (optional).
▪ Health Disparities. If applicable to the type of research project being
proposed, the Research Strategy must address how health disparity
populations or data will be integrated into the proposed studies.
PHS 398 Research Plan (FOA Part 2, Section IV):
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Addressing the Cancer Moonshot Public Access and Data Sharing Policy:
▪ Utilizing the provision outlined in the 21st Century Cures Act, NCI has
established a data sharing policy for projects that are funded as part of
the Beau Biden Cancer Moonshot Initiative that requires applicants to
submit a Public Access and Data Sharing Plan that describes their
proposed process for making resulting Publications and, to the extent
possible, the Underlying Primary Data immediately and broadly available to
the public upon publication or (if applicable) provides a justification to NCI if
such sharing is not possible.
▪ NCI will give competitive preference and funding priority to applications that
comply with the strategy described at NCI Cancer Moonshot℠ Public
Access and Data Sharing Policy website.
▪ The data sharing plan will become a term and condition of award.
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Administrative Core (cont.):
Budget:▪ The Administrative Core Leader is strongly encouraged to propose and
budget for a Center Administrator to manage day-to-day operations.
▪ The budget should include funds to support travel for Center and
FusOnC2 Consortium activities, including but not limited to:
▪ Supporting the participation of PD(s)/PI(s) in an initial FusOnC2
Consortium Kick-off Meeting.
▪ Supporting the participation of the PD(s)/PI(s) and other Center members
in an Annual Investigators' Meeting.
▪ FusOnC2 Centers are encouraged to include early career scientists in the
Consortium activities and should include budget to travel at least one
graduate student or postdoctoral fellow to the Annual Investigators’ Meeting.
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Administrative Core:
▪ Plans to coordinate and support the Projects within the FusOnC2 Center,
foster synergy within the Center, and support planning and evaluation
activities.
▪ Management and Communication Plan.
▪ Annual Meeting and Other Consortium Activities.
▪ Brief description of strategies for connecting and integrating the Center
with the broader FusOnC2 Consortium.
▪ Outreach plan.
▪ Promote training and development of researchers in the Center, and
disseminate advances and capabilities to broader research community.
▪ Center and Program Evaluation.
PHS 398 Research Plan should include (FOA Part 2, Section IV):
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Research Projects
▪ Each FusOnC2 Center should have 3-4 Research Projects
▪ Overall strategy for the Research Project
▪ Concise description of how it fits into organizing framework of the
FusOnC2 Center.
▪ Standard sub-sections (Significance, Innovation, and Approach).
▪ Project Timeline: A timeline (Gantt chart) including yearly milestones is
required.
PHS 398 Research Plan should include (FOA Part 2, Section IV):
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Shared Resource Cores (optional)
▪ If included, must support at least 2 Research Projects.
▪ May be physical or virtual infrastructure providing a resource that supports
other Center components in their activities. The services and resources
provided to other Center components should be clearly defined.
▪ Issues to be addressed include, but are not limited to: value of the Core
services to the Center and Research Projects, integration between the Core
and Projects, quality control, procedures for selecting Projects to use the Core
and allocating resources, cost effectiveness, and increased efficiency.
▪ Training in complex techniques and methods should be described if they are
functions of the proposed Core.
▪ These shared resources must not duplicate analogous resources already
established in the applicant institutions (although supplemental funding to
such existing resources may be requested).
Scientific Review
▪ Reviewers will provide an overall impact score for the entire FusOnC2
Center (Overall Component) and for each individual Research Project.
▪ In addition, assigned reviewers will provide individual "criterion scores"
for the Overall criteria and for the Research Projects criteria, but not for
the other components.
▪ The Administrative Core and optional Shared Resource Cores will be
evaluated, but each will receive only one overall adjectival (not
numerical) rating.
▪ For the evaluation of the FusOnC2 Center application, the Research
Projects will be emphasized as the scientific base of each Center, with
additional components enhancing and integrating the overall research
program.
Scientific Review (continued)
▪ These grants have additional review criteria (see RFA)
▪ Appeals of initial peer review will not be accepted.
▪ Recommended applications will receive a second level of review by the
National Cancer Advisory Board.
The following will be considered in making funding decisions:
▪ Scientific and technical merit of the proposed project as determined by
scientific peer review.
▪ Availability of funds.
▪ Relevance of the proposed project to program priorities.
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Agency Contacts (See FOA Section VII)
Malcolm Smith, M.D., Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute (NCI)
Telephone: 240-276-6087
Email: [email protected]
Keren Witkin, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6250
Email: [email protected]
Scientific/Research Contacts:
Charles Morrow, M.D., Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-408-9850
Email: [email protected]
Financial/Grants Management Contact:
Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: [email protected]
Peer Review Contact:
www.cancer.gov www.cancer.gov/espanol
Slides will be posted on the NCI DCB website:
https://www.cancer.gov/about-nci/organization/dcb
